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1.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
Importance
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
Objective
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Participants
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Interventions
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Results
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
doi:10.1001/2013.jamaneurol.405
PMCID: PMC3771392  PMID: 23400560
2.  Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach 
AIDS (London, England)  2013;27(9):1473-1481.
Objective
CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown.
Design
A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow-up in relation to AIDS progression.
Methods
Percentages of CD4 and CD8 T cells with HLA-DR± and CD38± were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR± and CD38±) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership.
Results
Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8+CD38– DR– (average = 41% of total CD8 T-cell pool), CD4+CD38– DR– (average = 53% of total CD4 T-cell pool), and CD8+CD38– DR+ (28%); Cluster 2: higher CD8+CD38+DR– (44%) and CD4+CD38+DR– (58%); Cluster 3: higher CD8+CD38+DR+ (49%) and CD4+ CD38+DR– (48%); Cluster 4: higher CD8+CD38+DR+ (49%), CD4+CD38+DR+ (36%) and CD4+CD38– DR+ (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio = 2.13; 95% confidence interval = 1.30–3.50) adjusted for CD4 cell count, HIV RNA, and other confounders.
Conclusion
A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression.
doi:10.1097/QAD.0b013e3283601bad
PMCID: PMC3949252  PMID: 23945505
AIDS; cluster analysis; immune activation
3.  Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine 
AIDS (London, England)  2012;26(16):2097-2106.
Objective
CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
Design
The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
Methods
Five putative functional polymorphisms were tested for associations with virologic suppression within one year after NNRTI initiation in women naïve to antiretroviral agents (n=91). Principal components (PCs) were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
Results
Rs3745274 was significantly associated with virologic suppression (OR=3.61, 95% CI 1.16-11.22, p trend=0.03); the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66-infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for PCs (p trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
Conclusion
The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted given the potential clinical importance of this finding.
doi:10.1097/QAD.0b013e3283593602
PMCID: PMC3940150  PMID: 22951632
CYP2B6; population substructure; women; NNRTIs; confounding
4.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
Objective
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Conclusions
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
doi:10.1161/ATVBAHA.112.300346
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
6.  Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults 
Circulation  2012;126(13):1614-1620.
Background
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.
Methods and results
The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and socio-demographic characteristics and a 12-hr fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (± 54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12) O3 exposure was associated with a 7.8 μm (95% CI −0.3, 15.9) or 10.1 μm (95% CI 1.8, 18.5) higher CIMT, respectively. Lifetime exposure to O3 showed similar but non-significant associations. No associations were observed for PM2.5, PM10 or NO2 although adjustment for these pollutants strengthened the childhood O3 associations.
Conclusion
Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
doi:10.1161/CIRCULATIONAHA.112.096164
PMCID: PMC3474843  PMID: 22896588
atherosclerosis; cardiovascular diseases; carotid arteries; epidemiology; pediatrics
7.  Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection 
The Journal of Infectious Diseases  2012;206(5):780-789.
Background.Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non–AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART).
Methods.A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2–4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation.
Results.Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation.
Conclusions.Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
doi:10.1093/infdis/jis380
PMCID: PMC3491747  PMID: 22693231
8.  Insulin Resistance and Cognition Among HIV-Infected and HIV-Uninfected Adult Women: The Women's Interagency HIV Study 
Abstract
Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV+) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78 s (95% CI: 0.48–7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.
doi:10.1089/aid.2011.0159
PMCID: PMC3332367  PMID: 21878059
9.  Impact of angiotensin receptor blockers on Alzheimer's disease neuropathology in a large brain autopsy series 
Archives of neurology  2012;69(12):1632-1638.
Background
Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers (ARB) may also prevent cognitive decline. We evaluated the impact of ARBs on the neuropathology in the National Alzheimer’s Coordinating Center (NACC) database which includes aggregated data and brain autopsies from 29 Alzheimer’s Disease Centers throughout the USA.
Methods
Data from Participants were self- or provider-referred and included those with and without cognitive disorders. Our sample included hypertensive participants and excluded cognitively and neuro-pathologically normal participants (n=890, mean (range) age at death 81 (39–107) years, 43% women, 94% white). Neuropathological data included neuritic plaque and neurofibrillary tangle densities assessed by NIA-Reagan criteria and vascular injury markers. Multiple logistic regression was used to compare the pathological findings in subjects on ARBs to other antihypertensive treatment and to those who did not receive antihypertensive medications.
Results
Participants who were exposed to ARBs, with or without AD, showed less amyloid deposition markers compared to those treated with other antihypertensives (lower CERAD OR=0.47, 95% confidence interval =0.27 to 0.81; ADRDA OR=0.43, CI=0.21 to 0.91; BRAAK & BRAAK OR=0.52, CI= 0.31 to 0.85; neuritic plaques OR=0.59, CI=0.37 to 0.96). They also had less AD-related pathology compared to untreated hypertensives. Participants receiving ARBs were more likely to have had a stroke and hence had more frequent pathological evidence of large vessel infarct and hemorrhage.
Conclusion
Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs on cognitive decline in those with dementia or AD needs further investigation.
doi:10.1001/archneurol.2012.1010
PMCID: PMC3608189  PMID: 22964777
10.  Retinal Microvascular Abnormalities and Cognitive Function in Latino Adults in Los Angeles 
Ophthalmic epidemiology  2012;19(3):127-136.
Purpose
Retinal vessels may provide a readily accessible surrogate approach to study vascular disease in brain small vessels. Previous epidemiologic studies of retinal microvascular abnormalities and cognition have not included large numbers of Latinos who have a high prevalence of diabetes and hypertension.
Methods
We used data from 809 elderly Latino participants in the Los Angeles Latino Eye Study (LALES) to assess whether retinal vessel caliber and microvascular abnormalities are cross-sectionally associated with lower cognitive function. Cognitive screening was conducted with the Cognitive Abilities Screening Instrument-Short form (CASI-S) and in-depth testing with the Spanish English Neuropsychological Assessment Scales (SENAS). Retinal photographs were used to identify retinopathy signs and measure retinal vessel caliber.
Results
A total of 65.8% had high blood pressure, 34.5% had diabetes; self-reported diagnoses of heart attack, heart failure, angina and stroke were rare. Retinal calibers and any retinopathy were not associated with the CASI-S, total SENAS or any SENAS cognitive factors assessed as continuous variables. The odds of a low CASI-S score were two times higher in subjects with generalized arteriolar narrowing (OR = 2.04, 95% CI = 1.14, 3.66), and one and half times as high in those with both generalized arteriolar narrowing and retinopathy signs (OR = 1.49, 95% CI = 0.47, 4.75) though this result was based on only four cases with both risk factors and confidence limits were wide and included the null.
Conclusion
Retinal microvasculature imaging may provide insights into small blood vessel influences on cognition in Latino populations. Additional studies in diverse populations and prospective settings are needed.
doi:10.3109/09286586.2011.615452
PMCID: PMC3598630  PMID: 22568425
Epidemiology; Cognition; Retina; Latinos; Microvasculature
11.  CHRONIC DEPRESSIVE SYMPTOMS AND FRAMINGHAM CORONARY RISK IN HIV- INFECTED AND UNINFECTED WOMEN 
AIDS Care  2011;24(3):394-403.
Depression is common in people with cardiovascular diseases (CVD) and those with HIV, and is a risk factor for CVD-related mortality. However, little is known about whether HIV influences the relationship between depression and cardiovascular risk. 526 HIV-infected and 132 uninfected women from the Women’s Interagency HIV Study were included in an analysis of women who completed twice-yearly study visits over 9.5 years. CVD risk was calculated at baseline and approximately 9.5 years later using the Framingham Risk Score (FRS). Chronic depressive symptoms were defined as Center for Epidemiologic Studies Depression Scale scores of 16 or greater at ≥75% of study visits. Over the follow-up period, 22.8% of HIV-infected women and 15.9% of HIV-uninfected women had chronic depressive symptoms (p=0.08). Baseline FRS were similar between HIV infected and uninfected women (M=−5.70±SE=0.30 vs. M=−6.90± SE=0.60, p=0.07) as was follow-up FRS (M=0.82±SE=0.30 vs. M=−0.44± SE=0.73, p=0.11). Among HIV-infected and uninfected women, together, follow-up FRS were higher among women with chronic depressive symptoms as compared to those without (M=1.3± SE=0.6 vs. M=−0.3± SE=0.40, p<0.01), after adjusting for baseline FRS and other covariates. HIV status did not modify the relationship between chronic depressive symptoms and FRS. Chronic depressive symptoms accelerated CVD risk scores to a similar extent in both HIV infected and uninfected women. This implies that the diagnosis and treatment of depression may be an important consideration in CV risk reduction in the setting of HIV-infection. The determination of factors that mediate the depression/CVD relationship merits further study.
doi:10.1080/09540121.2011.608791
PMCID: PMC3243818  PMID: 21902560
12.  Coronary Artery Disease is Associated with Cognitive Decline Independent of MRI Changes in Cognitively Normal Elderly 
BACKGROUND/OBJECTIVES
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
DESIGN
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
SETTING
Memory and aging centers in California
PARTICIPANTS
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
MEASUREMENTS
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
RESULTS
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
CONCLUSION
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
doi:10.1111/j.1532-5415.2011.03839.x
PMCID: PMC3302932  PMID: 22283410
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
13.  Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization 
Menopause (New York, N.Y.)  2011;18(11):1172-1177.
Objective
Millions of women in the United States and across the globe abruptly discontinued postmenopausal hormone therapy (HT) after the initial Women’s Health Initiative trial publication. Few data describing the effects of HT cessation on hip fracture incidence in the general population are available. We evaluated the impact of HT cessation on hip fracture incidence in a large cohort from the Southern California Kaiser Permanente health management organization.
Methods
In this longitudinal observational study, 80,955 postmenopausal women using HT as of July 2002 were followed up through December 2008. Data on HT use after July 2002, antiosteoporotic medication use, and occurrence of hip fracture were collected from the electronic medical record system. Bone mineral density (BMD) was assessed in 54,209 women once during the study period using the dual-energy x-ray absorptiometry scan.
Results
After 6.5 years of follow-up, age- and race-adjusted Cox proportional hazard models showed that women who discontinued HT were at 55% greater risk of hip fracture compared with those who continued using HT (hazard ratio, 1.55; 95% CI, 1.36–1.77). Hip fracture risk increased as early as 2 years after cessation of HT (hazard ratio, 1.52; 95% CI, 1.26–1.84), and the risk incrementally increased with longer duration of cessation (P for trend < 0.0001). Longer duration of HT cessation was linearly correlated with lower BMD (β estimate [SE]) = −0.13 [0.003] T-score SD unit per year of HT cessation; P < 0.0001).
Conclusions
Women who discontinued postmenopausal HT had significantly increased risk of hip fracture and lower BMD compared with women who continued taking HT. The protective association of HT with hip fracture disappeared within 2 years of cessation of HT. These results have public health implications with regard to morbidity and mortality from hip fracture.
doi:10.1097/gme.0b013e31821b01c7
PMCID: PMC3511047  PMID: 21775911
Hormone therapy; Hip fracture; Bone mineral density; Women’s Health Initiative
14.  Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women 
Journal of neurovirology  2011;17(5):469-476.
Despite use of HAART, cognitive impairment remains prevalent in HIV. Indeed, a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. Participants were members of the Women’s Interagency HIV Study (WIHS). In analysis of cross-sectional data using general linear models we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI: 3.5 to 17.5, p = 0.003, N = 1130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1130). Summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.
doi:10.1007/s13365-011-0052-3
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
15.  Factors associated with hepatitis C viremia in a large cohort of HIV-infected and - uninfected women 
Background
Coinfection with hepatitis C virus (HCV) is common among HIV-infected women.
Objective
To further our understanding of the risk factors for HCV viremia and the predictors of HCV viral load among women.
Study design
We investigated sociodemographic, immunologic, and virologic factors associated with presence and level of HCV viremia among 882 HIV-infected and 167 HIV-uninfected HCV-seropositive women at entry into the Women's Interagency HIV Study.
Results
Plasma HCV RNA was detected in 852 (81%) of these 1,049 women (range: 1.2–7.8 log10 copies/ml). HCV-viremic women were more likely to have an HIV RNA level >100,000 copies/ml (P =0.0004), have reported smoking (P =0.01), or to be Black (P =0.005). They were less likely to have current or resolved hepatitis B infection. HCV RNA levels were higher in women who were >35 years old, or HIV-infected. Current smoking and history of drug use (crack/freebase cocaine, marijuana, amphetamines, or heroin) were each associated with both presence and level of viremia.
Conclusions
Substance abuse counseling aimed at eliminating ongoing use of illicit drugs and tobacco may reduce clinical progression, improve response to treatment, and decrease HCV transmission by lowering levels of HCV viremia in women.
doi:10.1016/j.jcv.2007.08.021
PMCID: PMC3493623  PMID: 18243785
Hepatitis C; Hepatitis C RNA levels; Hepatitis C viremia; HIV/hepatitis C virus coinfection
16.  Isoflavone Soy Protein Supplementation and Atherosclerosis Progression in Healthy Postmenopausal Women: A Randomized Controlled Trial 
Background and Purpose
Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness (CIMT) progression.
Methods
In a double-blind, placebo-controlled trial, 350 postmenopausal women 45–92 years of age without diabetes and cardiovascular disease (CVD) were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7-years.
Results
Overall, mean (95% confidence interval) CIMT progression rate was 4.77(3.39–6.16) μm/year in the ISP group and 5.68(4.30–7.06) μm/year in the placebo group. Although CIMT progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (p=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower CIMT progression rate than placebo participants 2.16(−1.10–5.43) vs. 6.79(3.56–10.01) μm/year, p=0.05). ISP supplementation had a null effect on women who were >5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation.
Conclusion
ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggest that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for CVD who were <5 years postmenopausal. These first trial results of their kind warrant further investigation.
doi:10.1161/STROKEAHA.111.620831
PMCID: PMC3202054  PMID: 21903957
Atherosclerosis; Cardiovascular disease; Intima-media thickness; Isoflavones; Menopause; Soy; Women
17.  Progression of Carotid Intima-Media Thickness in a Contemporary Human Immunodeficiency Virus Cohort 
Carotid artery intima-media thickness progression is associated with human immunodeficiency virus replication as well as with exposure to certain antiretroviral therapy regimens.
Background. Persons with human immunodeficiency virus (HIV) infection are at risk for premature cardiovascular disease (CVD). Predictors of atherosclerotic disease progression in contemporary patients have not been well described.
Methods. Using data from a prospective observational cohort of adults infected with HIV (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy), we assessed common carotid artery intima-media thickness (CIMT) at baseline and year 2 by ultrasound. We examined HIV-associated predictors of CIMT progression after adjusting for age, sex, race/ethnicity, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol level, and baseline CIMT using linear regression.
Results. Among 389 participants (median age at baseline, 42 years; male sex, 77%; median CD4+ cell count at baseline, 485 cells/mm3; 78% receiving antiretroviral therapy), the median 2-year CIMT change was 0.016 mm (interquartile range, −0.003 to 0.033 mm; P < .001). Lesser CIMT progression was associated with a suppressed viral load at baseline (−0.009 mm change; P = .015) and remaining virologically suppressed throughout follow-up (−0.011 mm change; P < .001). After adjusting for additional risk factors and a suppressed viral load during follow-up, nonnucleoside reverse transcriptase inhibitor versus protease inhibitor exposure was associated with lesser CIMT progression (−0.011 mm change; P = .02).
Conclusions. Suppressing HIV replication below clinical thresholds was associated with less progression of atherosclerosis. The proatherogenic mechanisms of HIV replication and the net CVD benefit of different antiretroviral drugs should be a focus of future research.
doi:10.1093/cid/cir497
PMCID: PMC3174096  PMID: 21860012
18.  Physical Activity and Sex Hormone Levels in Estradiol- and Placebo-Treated Postmenopausal Women 
Menopause (New York, N.Y.)  2011;18(10):1079-1086.
Objective
Postmenopausal changes in the hormonal milieu in women with or without hormone therapy (HT) are hypothesized to be the pathway for a number of menopause-associated modifications in physiology and disease risk. Physical activity may modify these changes in women’s hormone profiles. The crucial yet complex relationship between physical activity and physiologic and pharmacologic sex hormone levels in postmenopausal women has not been investigated sufficiently.
Methods
Using structured recall, physical activity was assessed longitudinally over two years in 194 postmenopausal women (90 randomized to daily 1 mg 17β-estradiol and 104 to placebo) in the Estrogen in the Prevention of Atherosclerosis Trial. Levels of physical activity were correlated to serum sex hormone and serum hormone-binding globulin (SHBG) levels in each treatment group.
Results
In placebo-treated women, total energy expenditure was positively associated with sex hormone-binding globulin (SHBG) (p<0.001) and inversely associated with testosterones (total, bioavailable, free) and androstenedione (p<0.001 for all), as well as with estradiol (p=0.02). In estradiol-treated women, estradiol levels were inversely associated with total energy expenditure (p=0.002) and weekly hours spent in moderate or more vigorous physical activity (p=0.001).
Conclusion
Physical activity is associated with lower serum levels of estradiol in both HT-treated and untreated women. In placebo-treated women only, physical activity is associated with reduced androgen levels and elevated SHBG levels.
doi:10.1097/gme.0b013e318215f7bd
PMCID: PMC3183237  PMID: 21646925
Physical activity; sex hormones; estradiol; menopause
19.  Carotid artery intima-media thickness in college students: race/ethnicity matters 
Atherosclerosis  2011;217(2):441-446.
Objective
Racial/ethnic differences in common carotid artery intima-media thickness (CIMT) and in risk factors associated with CIMT have been predominantly observed in middle-aged and older individuals. We aimed to characterize racial/ethnic differences CIMT and other cardiovascular risk factors in a healthy, young-adult population.
Methods
College students were recruited as part of a study to characterize determinants of atherogenesis. Students were eligible if they were lifetime non-smokers, lived in the United States since six months of age, and attended high school in the United States. Blood pressure, heart rate, height, and weight were measured, B-mode carotid ultrasound was performed, questionnaires were administered and a 12-hr fasting blood sample was collected. Associations between CIMT and other variables were assessed in 768 students aged 18 to 25 years using linear regression analysis.
Results
In models adjusted for common cardiovascular risk factors, sex exhibited the strongest influence on CIMT, with men having 15.4 µm larger CIMT compared to women (95%CI 6.6, 24.2). Race/ethnicity was also strongly associated with CIMT. African Americans had 17.3 µm greater CIMT (95% CI −0.3, 34.8) compared to non Hispanic Whites, whereas Asians and Hispanic Whites had 14.3 (95%CI −24.3, −4.4) and 15.4 (95%CI −26.2, −4.7) µm smaller CIMT, respectively. BMI and systolic blood pressure were positively associated with CIMT.
Conclusion
The risk factors associated with atherogenesis later in life are already present and observable in college-aged young adults, so targeted campaigns to reduce life-long cardiovascular disease burden should be initiated earlier in life to improve public health.
doi:10.1016/j.atherosclerosis.2011.05.022
PMCID: PMC3146627  PMID: 21679950
CIMT; SBP; race; ethnicity; young adults
20.  Chinese-Language Montreal Cognitive Assessment for Cantonese or Mandarin Speakers: Age, Education, and Gender Effects 
The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1–6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7–11 and 12–20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers.
doi:10.1155/2012/204623
PMCID: PMC3399373  PMID: 22830073
21.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review 
Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.
doi:10.1186/alzrt98
PMCID: PMC3471388  PMID: 22182734
22.  Negative-Strand Hepatitis C Virus (HCV) RNA in Peripheral Blood Mononuclear Cells from Anti-HCV–Positive/HIV-Infected Women 
The Journal of Infectious Diseases  2006;195(1):124-133.
Background
Hepatitis C virus (HCV) has been reported to replicate in peripheral blood mononuclear cells (PBMCs), particularly in patients coinfected with HCV and human immunodeficiency virus (HIV). However, there are limited data regarding the prevalence of and the factors associated with extrahepatic replication.
Methods
The presence of negative-strand HCV RNA in PBMCs was evaluated by a strand-specific assay for 144 anti-HCV–positive/HIV-infected women enrolled in the Women’s Interagency HIV Study. One to 5 PBMC samples obtained from each woman were tested. Multivariate analyses were used to assess for associations with the clinical and demographic characteristics of the women.
Results
Negative-strand HCV RNA was detected in 78 (25%) of 315 specimens, and, for 61 women (42%), ≥1 specimen was found to have positive results. The presence of negative-strand HCV RNA in PBMCs was significantly positively associated with an HCV RNA plasma level of ≥6.75 log copies/mL (P =.04) and consumption of ≥7 alcoholic drinks per week (P =.02). It was also negatively associated with injection drug use occurring in the past 6 months (P =.03). A negative association with a CD4+CD38+DR+ cell percentage of >10% and a positive association with acquired immunodeficiency syndrome were borderline significant (P =.05).
Conclusions
HCV replication in PBMCs is common among HIV-coinfected women and appears to be a dynamic process related to lifestyle, virologic, and immunologic factors.
doi:10.1086/509897
PMCID: PMC3319123  PMID: 17152016
23.  Cognitive Effects of Atypical Antipsychotic Medications in Patients with Alzheimer’s Disease: Outcomes from CATIE-AD 
The American Journal of Psychiatry  2011;168(8):831-839.
Objective
The impact of the atypical antipsychotics, olanzapine, quetiapine and risperidone on cognition in patients with Alzheimer’s disease is unclear. This report describes the effects of time and treatment on neuropsychological function during the Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease study (CATIE-AD).
Method
CATIE-AD included 421 Alzheimer’s disease outpatients with psychosis or agitated/aggressive behavior, randomized to masked, flexible-dose olanzapine, quetiapine, risperidone or placebo. Based on clinician’s judgment, patients could discontinue originally assigned medication and be randomized to another medication. They were followed for 36 weeks. Cognitive assessments were obtained at baseline, 12 weeks, 24 weeks and 36 weeks. Outcomes were compared among 357 patients with baseline and at least one follow-up cognitive measure obtained while on their prescribed medication or placebo for at least 2 weeks before cognitive testing.
Results
Overall, patients showed steady, significant declines over time in most cognitive areas, including Mini-mental State Examination (2.4 points over 36 weeks) and Alzheimer’s Disease Assessment Scale-cog (4.4 points). Patients on antipsychotics declined more than patients on placebo on multiple cognitive measures, including the MMSE (p=0.004), BPRS cognitive subscale (p=0.05), and a cognitive summary score summarizing change on 18 cognitive tests (p=0.004).
Conclusions
In CATIE-AD atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with one year’s deterioration compared with placebo. Further cognitive impairment is an additional risk of atypical antipsychotic treatment for Alzheimer’s disease patients that should be considered when considering treatment.
doi:10.1176/appi.ajp.2011.08121844
PMCID: PMC3310182  PMID: 21572163
24.  A “Window of Opportunity:” The Reduction of Coronary Heart Disease and Total Mortality with Menopausal Therapies is Age and Time Dependent 
Brain research  2010;1379:244-252.
The totality of data indicate that the “window of opportunity” for reducing coronary heart disease (CHD) and overall mortality is initiation of hormone therapy (HT) within 6 years of menopause and/or before 60 years of age. Reduction of CHD risk and overall mortality with prolonged HT use in this subgroup of women is consistent across randomized controlled trials and observational studies. As such, HT use for 5 to 30 years in postmenopausal women who initiate HT in their 50s substantially increases quality-adjusted life-years (QALYs) by 1.5 QALYs and is highly cost-effective at $2,438 per QALY gained. Cumulated randomized controlled trial results indicate a consistency along with observational data that young postmenopausal women with menopausal symptoms who use HT for long periods of time have lower rates of CHD and overall mortality than comparable postmenopausal women who do not use HT.
doi:10.1016/j.brainres.2010.10.076
PMCID: PMC3046231  PMID: 20977895
25.  Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles 
PLoS ONE  2012;7(2):e31267.
This study investigated the impact of chronic exposure to continuous (CoP4) versus cyclic progesterone (CyP4) alone or in combination with 17β-estradiol (E2) on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX) led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1), redox homeostasis (peroxiredoxin 5; Prdx5), insulin signaling (insulin-like growth factor I; Igf1), and cholesterol trafficking (liver X receptor α subtype; Nr1h3), differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX) and E2+CyP4 (up-regulation relative to OVX). In contrast, genes involved in amyloid metabolism (β-secretase; Bace1) differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1). In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT) can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.
doi:10.1371/journal.pone.0031267
PMCID: PMC3290616  PMID: 22393359

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